Protein tyrosine kinases (PTKs) are kinases that catalyze the transfer of γ-phosphates on adenosine triphosphates (ATPs) to tyrosine residues of proteins. It is known that the protein tyrosine kinase (PTK) signaling pathways play an important role in growth, proliferation, differentiation, metabolism and apoptosis of cells.
PTKs include a receptor type and a non-receptor type. Receptor type PTKs include nine sub-types based on their structures, of which an epidermal growth factor receptor (EGFR) family, a vascular endothelial growth factor receptor (VEGFR) family, a platelet-derived growth factor receptor (PDGFR) family, a fibroblast growth factor receptor (FGFR) family and an insulin receptor (INSR) family are common. Non-receptor type PTKs are completely intracellular PTKs, also known as “cell tyrosine kinases”, of which a steroid receptor coactivator (SRC) family is common.
Interactions between growth factors and their receptors are necessary for the normal regulation of cell growth. However, under certain conditions, due to mutation or over-expression, inappropriate or uncontrolled activation of these receptors, i.e., aberrant protein tyrosine kinase activity may result in uncontrolled cell growth, which may cause tumor growth. For example, members of the EGFR family are particularly important growth factor receptor tyrosine kinases associated with epidermal cell tumorigenesis. EGFR are overexpressed in many kinds of epidermal tumor cells. A VEGFR family is also a factor associated with cell tumorigenesis.
Overexpressed or mutated protein tyrosine kinases are associated with cancers. Consequently, inhibiting protein tyrosine kinases will be of significance in treating cancers. Currently, various small molecule tyrosine kinase inhibitors, such as GLEEVEC, TARCEVA, IRESSA, SUNITINIB and the like, have been used successfully in clinical treatments as anti tumor drugs.
Besides tumors, tissue and organ fibrosis is another disease seriously endangering human health. Fibrosis refers to the excessive deposition of fibrous connective tissues and the like, which results from imbalance between proliferation and degradation of fibrous tissues. One common feature of such diseases is over proliferation of fibroblasts. Currently, tissue and organ fibrosis commonly include pulmonary fibrosis, hepatic fibrosis, chronic pancreatitis, scleroderma, renal glomerular fibrosis, and multiple organ fibrosis supervened with radiochemotherapy and tissue transplantation, etc.
Previous studies have shown that FGFRs play a role in binding fibroblast growth factors and transferring signals thereof. This kind of signal transduction is associated with proliferation and differentiation of various types of cells. Excessive autocrine of fibroblast growth factors results in many diseases. Furthermore, abnormal signal transduction mediated by FGFRs is closely associated with fibrosis diseases.
Aberrant protein tyrosine kinase activity is also implicated in a variety of other disorders, such as inflammation, immune diseases, cardiovascular diseases, asthma, and nervous system diseases. Although numerous small molecular tyrosine kinase inhibitors have been developed for treatment and prophylaxis of various protein tyrosine kinases associated diseases, a need for new tyrosine kinase inhibitors for the treatment and/or prophylaxis of protein tyrosine kinases associated diseases, particularly for the treatment and/or prophylaxis of tumors and fibroblast proliferation associated diseases, still exists.